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LAS VEGAS -- Children and teens with Crohn's disease who received early tumor necrosis antagonist (anti-TNF) treatment had a lower risk of developing perianal fistulizing complications (PFCs) than those who received no immunosuppression or immunomodulators without TNF inhibitors, according to a post-hoc analysis of a prospective observational study.

Treatment with TNF inhibitors was linked with 83% lower odds (OR 0.17, 95% CI 0.05-0.57, P=0.0041) of developing PFCs compared to no immunomodulating treatment and 78% lower odds (OR 0.22, 95% CI 0.0540-0.90, P=0.035) compared to immunomodulators without anti-TNF therapy in propensity-matched patients, reported Jeremy Adler, MD, MSc, of the University of Michigan in Ann Arbor.

Presence of perianal lesions, meanwhile, more than tripled the odds of PFCs (OR 3.86, 95% CI 1.58-9.42, P=0.003), Adler reported at the Crohn's & Colitis Congress.

The incidence of perianal fistula development in children is about 30% by 6 years after Crohn's diagnosis, Adler said, and they're more common in non-white and in Hispanic patients.

"They're difficult to treat, they commonly reoccur, they affect the quality of life, and they increase costs of care three- to four-fold, depending on the study you're looking at," Adler said. Evidence from retrospective studies suggests "perianal fistulas may actually be preventable" through early treatment, he noted, "and it would be far better to prevent these complications than to treat them once they occur."

This study analyzed data from 447 patients, under age 18 years, who were prospectively enrolled in the between 2008-2012 from 28 North American sites. Patients were excluded if they had PFCs, defined as perianal fistula or abscess, at or before enrollment, but the study included patients with perianal lesions, including skin tags or fissures.

Researchers divided the patients into three mutually exclusive groups based on treatment and then tracked them from enrollment until 3 months before PFC development or 3 months before the end of the study. The three groups included those receiving no immunosuppressive drugs; those taking immunomodulators, such as thiopurines or methotrexate, but no anti-TNF therapy; and those taking TNF inhibitors with or without immunomodulators or other medications.

Propensity score-matching was used to match patients across those groups by gender, age at diagnosis, growth delay, deep endoscopic ulcers, small bowel involvement, and inflammatory burden (high, medium or low), based on a combined variable of the weighted pediatrics Crohn's disease activity index (wPCDAI), platelets, albumin, erythrocyte sedimentation rate (ESR) and c-reaction protein (CRP). The initial population included 873 patients, but after propensity-score matching, each group had 149 patients.

Compared to predicted probability of PFC development over 3 years, early anti-TNF treatment reduced risk of PFCs by 64% (P=0.0041), compared to no immunomodulating therapy, before propensity matching. Compared to immunomodulators alone, risk of PFCs with anti-TNF therapy was 43% lower (P=0.035), and immunomodulators alone did not significantly reduce risk of PFCs at all (P=0.59). In the matched cohort, odds shifted to show a greater reduction in risk of PFCs during anti-TNF therapy.

"If you look at the predictors of which patients developed the perianal fistulas, the one significant predictor was did they or did they not have perianal lesions -- this is skin tags or fissures," Adler said. "They have almost four-fold increased risk of developing perianal fistulas," and the only treatment with significance was early anti-TNF medication use. Patients with perianal lesions who received anti-TNF therapy had 96% lower odds (OR 0.04, 95% CI 0.0053-0.36, P=0.035) of developing PFCs compared to no therapy while immunomodulators alone showed no reduced risk (P=0.10).

Though the patients were prospectively enrolled in the study, the findings were limited by a post-hoc analysis in a dated cohort, when treatment paradigms were different and it was common to delay the start of anti-TNF therapy, Adler said. The researchers also lacked data on race/ethnicity and anti-TNF dosing, and no therapeutic drug monitoring occurred.

Rebecca Gordon, MD, of Boston Children's Hospital, called the study very interesting and said the findings had clinical implications even for pediatric clinicians who are not gastroenterologists.

"The fact that what you do earlier on in the disease can have impacts years later is not surprising," particularly given how common fistula is in children with inflammatory bowel disease, said Gordon, who was not involved in the study.

"Knowing that there's a potential intervention we can do that would decrease the risk that is very helpful clinically," she said. The message for pediatricians is not to wait to refer children to a GI specialist since early treatment can make a difference long term.

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